The finding of the study noted in this news article has focused and broad implications. Amongst many progresses in oncology, the development of growth factors has made it possible to deliver chemotherapy with a lowered incidence of myelosuppression and related infections. But still, blood count recovery duration and intensity cannot be predicted due to lack of a standardized biomarker. During the time of myelosuppression, there is always a chance of life-threatening infections. Predicting this duration and intensity of myelosuppression can be lifesaving -- which is true for any myelosuppressive therapy.

On the other hand, telomeres are repetitive DNA sequences (TTAGGG) at the natural end of linear chromosomes, important to avoiding genomic instability and maintaining chromosomal integrity by avoiding degradation. Aging, cell division, and the malignant process shorten the length of the telomeres. The length of the telomere is maintained by telomerase enzyme complex.

In cancer, the telomerases are overactive. Multiple studies have looked into the association between the length of telomeres in peripheral blood leukocytes and the risk of cancer, but without convincing evidence. Studies have also shown prognostic significance of short telomeres in various cancers.

Pediatric acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. In this study, the investigators examined the telomere length in bone marrow biopsy of children in remission after second-induction treatment for AML. Quantitative polymerase chain reaction (q-PCR) was performed as a proxy to telomere length to determine the telomere content. Interestingly, short telomere content measured by q-PCR was associated with prolonged neutropenia after fourth and fifth chemotherapy courses. The telomere content was also independently predictive of neutrophil recovery.

This is a very intriguing and interesting finding. Predicting prolonged neutropenia and time to recovery of neutrophil count based on a biomarker seems realistic. The use of q-PCR to measure telomere content needs to be validated on a large patient cohort and will also need standardization. The future will also tell us if the telomere length can be predictive for other cancers.

Full Critique

Up to 19% of children with newly diagnosed acute myeloid leukemia (AML) treated with high-intensity chemotherapy with or without allogeneic hematopoietic stem-cell transplantation (HSCT) die from a treatment-related complication, such as sepsis or invasive infections acquired during profound and prolonged myelosuppression.

The factors associated with slow recovery of bone marrow in some but not all patients following chemotherapy for AML have been unclear, but a team of U.S. and Canadian investigators has discovered a potential method for identifying patients at highest risk for delays. The method involves measuring telomere content (TC), a surrogate for telomere length, as a means of determining an individual patient's hematopoietic stem cell (HSC) reserve following intensive therapy.

"Our results suggest that less TC reflects stress on the HSC pool induced by serial courses of intensive chemotherapy," Maria M. Gramatges, MD, PhD, of Baylor College of Medicine in Houston, and colleagues wrote online in the Journal of Clinical Oncology. "The contribution of other recognized HSC stressors such as infection or pro-inflammatory cytokines may further explain the differences in recovery time among individuals diagnosed with AML."

Chromosomal Sentinels

Telomeres are often likened to aglets, the small plastic or metal sheaths that keep the ends of shoelaces from fraying, but that analogy is both incomplete and misleading. Telomeres are in reality specialized DNA-protein structures that lie at the ends of chromosomes and help to protect against inaccurate repairs of double-stranded DNA breaks.

Gramatges and others had previously reported that less telomere content appears to be associated with risk of second cancers, especially thyroid cancers, among survivors of childhood malignancies.

In the new study, the team sought to determine whether telomere length in non-leukemic cells could be measured to assess the risk for significantly delayed recovery of bone marrow after AML therapy.

Quantitative polymerase chain reaction (qPCR) was used to measure the telomere content of cells from 115 children enrolled in the Children's Oncology Group AAML0531 study, a phase III randomized trial of gemtuzumab ozogamicin combined with conventional chemotherapy for de novo AML in children, adolescents, and young adults.

Children were randomized at study entry to receive either standard combination chemotherapy alone or with gemtuzumab, with two induction and three intensification cycles; some patients went on to have HSCT.

For the telomere analysis, the investigators looked at samples from 53 children with significantly delayed neutrophil recovery after chemotherapy, as well as 62 children with normal patterns of recovery.

Following both the fourth and fifth courses of chemotherapy, less telomere content was significantly associated with prolonged neutropenia, with respective P values of .001 and .002.

In a regression analysis model adjusted for age at diagnosis, telomere content remained an independent predictor of time to recovery of absolute neutrophil count (ANC) for both the fourth course (P=.002) and fifth course (P=.009) of chemotherapy.

"Our results suggest that less TC at the end of AML induction may predict delays in ANC recovery in later chemotherapy courses," the researchers said. "This association was not related to differences in host factors, telomere maintenance gene variants, AML disease characteristics, or therapeutic exposures such as GO."

Gramatges and colleagues noted that telomere content and the association with white blood cell counts could be measured prospectively in future studies with telomere flow fluorescent in situ hybridization.

Additionally, if the results can be validated in larger cohorts, they could offer clinicians a means of identifying patients at high risk for severe myelosuppression at the end of AML induction who may require closer monitoring or earlier or more aggressive prophylaxis of infectious complications.

The study was supported by an Alex's Lemonade Stand Young Investigator Award, St. Baldrick's Foundation Scholar Award, and National Institutes of Health grants. Gramatges reported having no disclosures. Two of her seven co-authors disclosed financial relationships with various companies.

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